Precursors of class I specific allo-CTL were found to be activated by at least two distinct populations of helper T cells: (1) L3T4+ Lyt2- helper T cells which were class II restricted, and (2) L3T4- Lyt2+ helper T cells which were class I restricted. The mechanism by which these two TH populations functioned were distinct since monoclonal antibody against the IL-2 receptors expressed by pCTL preferentially blocked the activation of pCTL by class II restricted helper T cells rather than class I restricted helper T cell. Thus, these results demonstrate the existence of two different classes of TH cells and two distinct helper mechanisms in the induction of class I specific allo-CTL responses.